The relationship between fatigue, pruritus, and thirst distress with quality of life among patients receiving hemodialysis: a mediator model to test concept of treatment adherence

Hemodialysis is a conservative treatment for end-stage renal disease. It has various complications which negatively affect quality of life (QOL). This study aimed to examine the relationship between fatigue, pruritus, and thirst distress (TD) with QOL of patients receiving hemodialysis, while also considering the mediating role of treatment adherence (TA). This cross-sectional study was carried out in 2023 on 411 patients receiving hemodialysis. Participants were consecutively recruited from several dialysis centers in Iran. Data were collected using a demographic information form, the Fatigue Assessment Scale, the Thirst Distress Scale, the Pruritus Severity Scale, the 12-Item Short Form Health Survey, and the modified version of the Greek Simplified Medication Adherence Questionnaire for Hemodialysis Patients. Covariance-based structural equation modeling was used for data analysis. The structural model and hypothesis testing results showed that all hypotheses were supported in this study. QOL had a significant inverse association with fatigue, pruritus, and TD and a significant positive association with TA. TA partially mediated the association of QOL with fatigue, pruritus, and TD, denoting that it helped counteract the negative association of these complications on QOL. This model explained 68.5% of the total variance of QOL. Fatigue, pruritus, and TD have a negative association with QOL among patients receiving hemodialysis, while TA reduces these negative associations. Therefore, TA is greatly important to manage the associations of these complications and improve patient outcomes. Healthcare providers need to assign high priority to TA improvement among these patients to reduce their fatigue, pruritus, and TD and improve their QOL. Further studies are necessary to determine the most effective strategies for improving TA and reducing the burden of complications in this patient population.


Literature review
Previous studies on patients receiving hemodialysis reported the inverse relationship of their QOL with their fatigue 52,53 , pruritus 18,54,55 , and TD 25,49,56 .The QOL of these patients is also affected by factors such as the longterm course of their treatment, complex treatment regimens, dermatologic manifestations, and lifestyle changes 57 .These findings denote that the effective management of these problems may improve patients' QOL.Respecting TA, different studies found a positive correlation with the QOL of patients receiving hemodialysis [58][59][60][61] .However, some studies reported no significant relationship between TA and QOL 62 .Moreover, there is limited data about the combined association of fatigue, pruritus, TD, and TA with QOL.Therefore, the current study was conducted in order to examine the inter-relationships of fatigue, pruritus, and TD with QOL and the potential mediating role of TA among patients receiving hemodialysis.
The conceptual framework of this study was the symptom management theory (SMT).This theory emphasizes the importance of symptom management to improve QOL 63 .The four components of this theory are symptom experience, symptom management strategies, outcomes, and influential factors on symptom management.This theory focuses on the perception and management of the symptoms that patients experience with chronic illnesses.It focuses on the dynamic and multidimensional characteristics of the symptoms while considering the complex interaction of biological, psychological, and social factors that influence symptom experience.It also provides a comprehensive approach to evaluate, measure, and manage symptoms to improve QOL among different patient populations.This theory considers symptom management as a complex and multidisciplinary phenomenon that needs the collaboration and interaction of healthcare providers, patients, and families 64,65 .SMT is a critical approach that aims to address and alleviate symptoms experienced by patients to enhance their QOL 66 .Specifically in the context of hemodialysis, this theory plays a crucial role in controlling common side effects such as fatigue, pruritus, and TD.By understanding the interconnected nature of symptoms and their impact on patient's well-being, healthcare providers can develop personalized interventions to effectively manage these symptoms.The theory underscores the significance of tailored and precise symptom management strategies to enhance patient outcomes [67][68][69] .
By utilizing the SMT, healthcare providers can implement comprehensive symptom management programs that address these side effects holistically.Through a systematic approach that takes into account the synergy between symptoms, providers can effectively classify and manage symptom clusters.This shift in focus from individual symptoms to interconnected symptom clusters allows for a more targeted and comprehensive management strategy 69,70 .
By understanding the relationships between symptoms such as fatigue, pruritus, and TD, healthcare providers can develop interventions that not only alleviate these side effects but also enhance treatment adherence.TA may serve as a mediating factor that helps mitigate the negative effects of symptoms on QOL.Therefore, by integrating the principles of SMT into practice, healthcare providers can optimize patient care by effectively controlling common side effects associated with hemodialysis, ultimately leading to improved patient outcomes 68,71 .

Research problems
Based on the literature and proposed conceptual model, the following hypotheses are raised: 1. Fatigue reduces the QOL of patients undergoing hemodialysis.2. Pruritus reduces the QOL of patients undergoing hemodialysis.3. TD reduces the QOL of patients undergoing hemodialysis.4. TA increases the QOL of patients undergoing hemodialysis.5.The mediating role of TA may explain the relationship between fatigue and QOL of patients undergoing hemodialysis.6.The mediating role of TA may explain the relationship between pruritus and QOL of patients undergoing hemodialysis.7. The mediating role of TA may explain the relationship between TD and QOL of patients undergoing hemodialysis.
Responding to these problems can help clarify if addressing adherence is crucial for improving patients' wellbeing beyond managing only the complications.

Design and participants
This cross-sectional study was carried out using structural equation modeling between September to October 2023.
The population of the study consisted of all patients with CKD who received hemodialysis.Participants were consecutively selected from four hospitals in Amol, Iran.Inclusion criteria were to be above eighteen years old and to have received hemodialysis for at least one year before the study.Exclusion criteria were peritoneal dialysis, kidney transplantation, emergency hemodialysis, and acute renal failure during the study.The sample size was calculated for structural equation modeling 72 with a moderate effect size of 0.25 73 , a power of 0.80, a confidence level of 0.95, five latent factors, and 48 items of the data collection instruments.Calculations showed that 229 participants were necessary.Nonetheless, considering an attrition rate of at least 10% due to missing data, the sample size was increased to 252 and finally, 411 patients were recruited to the study.The reliability of this survey in Iran for the general population has been thoroughly examined and confirmed.The Cronbach's alpha for the physical and mental components was found to be 0.730 and 0.720, respectively.This indicates a high level of internal consistency and reliability in the survey results 80 .The Cronbach's alpha, McDonald's omega, and an AIC of the scale in the present study were 0.803, 0.836, and 0.312, respectively.

A modified version of the Greek simplified medication adherence questionnaire for hemodialysis patients (GR-SMAQ-HD)
Alikari et al. developed this eight-item questionnaire in 2017 for patients receiving hemodialysis.Three items are Yes/No questions and five items are scored on a five-point Likert scale.Items are on the different aspects of TA, namely medication adherence, attendance at hemodialysis sessions, and fluid/diet restrictions.Items are scored either zero or 1 and hence, the possible range of the total score of the questionnaire is 0-8, where higher scores show greater TA 81 .In the present study, the Cronbach's alpha, McDonald's omega, and an AIC of items 1-4 were 0.734, 0.744, and 0.389, the Cronbach's alpha and an AIC of items 5 and 6 were 0.894 and 0.810, and the Cronbach's alpha and an AIC of items 7 and 8 were 0.582 and 0.412, respectively.

Data analysis
The Kaiser-Meyer-Olkin and Bartlett's tests were used to determine sampling adequacy and model appropriateness in factor analysis.Kaiser-Meyer-Olkin test values of more than 0.7 show model appropriateness 82 .The Mahalanobis distance was also used to find multivariate outliers 83 .Univariate normality was tested via skewness (± 3) and kurtosis (± 7) measures and multivariate normality was tested via the Mardia's coefficient (< 8) 83 .Finally, structural equation modeling was performed to assess the mediating role of TA in the relationship of fatigue, pruritus, and TD with QOL.Bootstrapping with 2000 repetitions was also employed for hypothesis testing in structural modeling 84  www.nature.com/scientificreports/from all subjects and/or their legal guardian(s).Permissions to use the data collection tools were acquired from their developers.All procedures adhered to the appropriate guidelines and regulations.

Results
None of the participants were excluded from the study and the data of all 411 recruited participants were analyzed.The participants' mean age was 59.37 (SD = ± 12.99) years (95% confidence interval: 58.11-60.63)and the percentage of men and women participants was almost equal (50.1% vs. 49.9%).Most participants reported that they had social support (78.10%).Table 1 shows participants' characteristics.
Findings revealed a significant indirect effect of TA in the relationships between fatigue and QOL (b = − 0.087, p-value < 0.001), between pruritus and QOL (b = − 0.305, p-value < 0.001), and between TD and QOL (b = − 0.208, p-value < 0.001) (Table 2 and Fig. 1). Figure 1 shows the full effect and depicts the results of the structural model assessment, in which the mediation model accounted for 35.4% of the variance of TA and 68.5% of the total variance of QOL.
Table 3 displays the reliability of the scales, and questionnaires, along with the factor loading of each item.Instruments showed acceptable reliability.Items 8 of the FAS, 5 of the 12-PSS, 2 and 5 of the TDS, and 3 of the GR-SMAQ-HD for hemodialysis patients were removed.

Discussion
The relationship between fatigue, pruritus, TD, and QOL among patients undergoing hemodialysis can be better understood through SMT, with TA playing a crucial role as a mediating variable.Fatigue, pruritus, and TD are common complications experienced by hemodialysis patients, significantly associated with their QOL.Research findings indicate that higher levels of fatigue, pruritus, and TD are linked to lower QOL scores, highlighting the detrimental impact of these complications on overall well-being.However, the positive correlation between TA www.nature.com/scientificreports/and QOL suggests that following treatment plans can help alleviate the negative effects of these complications on QOL.TA acts as a protective factor, reducing the adverse impact of complications and improving patient outcomes.
The finding revealed a significant negative relationship between fatigue and QOL.In line with this finding, patients receiving hemodialysis in a previous study reported impaired QOL due to the loss of energy, reduced cognitive and motor functioning, increased dependence, and reduced self-esteem 13 .Fatigue is a mental state of burnout with reduced motivation, altered social relationships, and reduced sleep quality and thereby, can reduce QOL among patients receiving hemodialysis.Chronic fatigue in hemodialysis patients may be attributed to anxiety, depression, and poor sleep quality.These factors can result in decreased motivation, changes in social interactions, and a diminished overall QOL for individuals undergoing hemodialysis treatment 85 .www.nature.com/scientificreports/ A study on patients receiving hemodialysis reported that anxiety and depression had a significant relationship with fatigue 86 .Anxiety and depression are prevalent among hemodialysis patients, significantly impacting their QOL.These conditions are closely linked to fatigue, demonstrating their collective influence on patient wellbeing.Individuals suffering from anxiety and depression are more prone to experiencing fatigue, highlighting the interconnected nature of these factors and their combined effect on QOL 87 .
Increased levels of the metabolites of tryptophan and the precursors of serotonin and melatonin among patients receiving hemodialysis are associated with depression and fatigue 88 .Moreover, sleep disorders among these patients threaten their general health, mental health, and physical capacity, and cause them fatigue.A study indicated a significant relationship between sleep disorders and fatigue among patients receiving hemodialysis and noted that the effective management of sleep disorders can reduce their fatigue and improve their QOL 89 .
Inadequate sleep quality is prevalent among hemodialysis patients and is associated with feelings of fatigue, anxiety, and depression.Issues such as insomnia and daytime sleepiness are frequently experienced by these individuals, exacerbating their fatigue and depression levels and ultimately affecting their overall QOL.It is crucial to address sleep disturbances, as well as effectively manage fatigue, anxiety, and depression, to enhance the well-being and QOL of hemodialysis patients 90 .Moreover, the elimination of waste products from the body during hemodialysis can also lead to hemodynamic instability, blood pressure fluctuations, electrolyte imbalances, and thereby, fatigue and energy loss 91 (Hypothesis-1).
We also found a significant inverse relationship between pruritus and QOL.This finding is consistent with the findings of a study that reported that uremic pruritus reduced sleep quantity and quality among patients receiving hemodialysis and thereby, reduced their QOL 54 .Patients with severe pruritus are more likely to stay awake at night, feel sleepy during the day, and have inadequate sleep 92 .A study also showed that dermatologic problems and altered body image due to pruritus and erosion reduced QOL among patients receiving hemodialysis 93 .Moreover, aesthetic problems and pruritus caused these patients occupational dysfunction and social isolation which in turn negatively affected their disease burden, daily life, and QOL 93 (Hypothesis-2).
Our findings also demonstrated a significant inverse relationship between TD and QOL.A study on patients receiving hemodialysis reported that fluid restriction caused these patients problems such as thirst, guilt, distress, and anxiety, while their constant exposure to thirst caused them fatigue and reduced their QOL 26 .Dryness of the mouth due to fluid restriction has a direct relationship with thirst and increases the risk of weight gain and orodental problems such as bacterial and fungal infections, candidiasis, dental caries, and periodontal diseases 94 .These problems cause difficulty in speaking, chewing, and eating, and thereby, greatly affect oral health and QOL 95 (Hypothesis-3).
Another finding of the present study was the significant positive relationship between TA with QOL.Similarly, a study showed that low medication adherence had a significant inverse correlation with physical QOL 96 .The close adherence of patients receiving hemodialysis to their treatment regimen significantly improves all dimensions of their QOL and reduces their vulnerability and hemodialysis complications.Moreover, adherence to dietary restrictions, fluid restrictions, and medications significantly reduces symptoms and medication side effects and thereby, improves QOL and hope among patients 43 .Close TA also allows patients receiving hemodialysis to have an active role in their care, improves their sense of control and empowerment, and enhances their mental well-being 97 (Hypothesis-4).
Findings also indicated that TA indirectly affects QOL through mediating the fatigue-QOL relationship.Because of treatment-induced fatigue, patients receiving hemodialysis feel energy depletion and physical exhaustion and need more energy and time to adhere to their strict treatment regimen 98 .Fatigue can also negatively affect patients' attendance at hemodialysis sessions, while timely attendance at the sessions can improve hemodialysis efficiency, reduce fatigue, and improve QOL .
We also found the indirect effect of TA on QOL through mediating the relationship between pruritus and QOL.Pruritus reduces sleep quality, increases fatigue, and thereby, negatively affects the different aspects of TA such as attendance at hemodialysis sessions 92 .Poor adherence to hemodialysis sessions and medications obviously increases the need for re-hospitalization, imposes added costs on patients and healthcare systems, and reduces patients' physical and mental QOL 100 .Conversely, close TA can reduce pruritus and discomfort and hence, improve QOL, social interactions, and self-confidence, and increase patients' ability to perform their daily activities 101 .On the other hand, effective management of pruritus enhances patient satisfaction with treatment which in turn improves their TA in a virtuous cycle and ultimately improves QOL and treatment outcomes 102 (Hypothesis-6).
We also found the significant mediating role of TA in the relationship of TD with QOL.Physiological symptoms such as TD and mouth dryness are one of the major barriers to adherence to fluid restriction 25 .Therefore, improving adherence to fluid restriction can reduce the overconsumption of fluids and weight gain between hemodialysis sessions and thereby, can maintain electrolyte balance and improve treatment outcomes 103 .Besides, adherence to dietary regimens, such as limited salt intake, can reduce TD which is a major contributing factor to fluid overconsumption 39 (Hypothesis-7).
The findings not only support the SMT but also highlight the crucial relationship between complications such as fatigue, pruritus, and TD, as well as TA, and QOL in hemodialysis patients.Improving TA is identified as a key strategy to reduce the negative impact of complications on QOL.This underscores the importance of comprehensive care approaches that focus on both symptom management and TA to enhance patient outcomes in this population.Healthcare providers should use these study results to improve patient outcomes by focusing on symptoms like fatigue, pruritus, and TD in hemodialysis patients.They can tailor interventions, emphasize TA, educate patients, monitor symptoms, and provide collaborative care to enhance QOL.By addressing these specific complications and promoting patient involvement in their care, healthcare providers can work towards better health outcomes for hemodialysis patients.

Limitations
Like all studies, this study had some limitations.For example, the study is limited by its cross-sectional design, which does not allow for causal conclusions to be reached.The sample size may be small and not representative of the larger population of patients undergoing hemodialysis.As study data were collected through the self-report method, fatigue might have affected participants' desire to participate in the study, and the accuracy, and concentration for answering the study instruments.We attempted to manage this limitation by providing participants with clear explanations about the study's aim and methods and providing them with adequate time to provide answers to the instruments.Moreover, some participants could not personally complete the study instruments due to problems such as arteriovenous fistula in the limb or low literacy level.We did our best to manage this limitation by involving their companions in data collection and using the interview method for data collection.

Conclusion
This study suggests that patients receiving hemodialysis can reduce their fatigue, pruritus, and TD and improve their QOL through close TA.Healthcare providers need to improve their knowledge about influential factors on QOL among these patients and employ appropriate interventions to improve their TA, reduce hemodialysisrelated complications, and improve their QOL and clinical conditions.Understanding the mediating role of TA can clarify how these complications are associated with QOL and offer valuable insights for developing targeted interventions, education, and strategies to improve QOL in hemodialysis patients.Additionally, comprehending the relationships of these factors with QOL allows patients to effectively communicate their experiences and seek appropriate support, ultimately leading to improved care and outcomes.It can also aid in developing evidencebased guidelines to manage complications and promoting adherence in hemodialysis patients.The results could change clinical guidelines and policies, through the management of complications for hemodialysis patients.This might include regular screening and incorporating complication management into care plans.

Recommendations
Further studies are necessary to assess the mediating role of the different dimensions of TA in the relationship of different hemodialysis complications with QOL.Moreover, the structural equation modeling approach used in the present study is recommended to assess the association of TA on patient outcomes among patients with cardiovascular disease, particularly hypertension.Studies on patients receiving hemodialysis are also necessary to assess the relationship of fatigue, pruritus, and TD with age, gender, and comorbid illnesses in order to identify patients who may be more susceptible to complications of hemodialysis.Adequate knowledge about these complications and their contributing factors helps healthcare providers use more effective strategies for fulfilling the unique needs of each patient and improving patient outcomes and QOL.
Longitudinal studies are needed to determine the relationship between fatigue, pruritus, TD, TA, and QOL.They can help researchers understand the underlying mechanisms and potential causal relationships between these factors, as well as the bidirectional relationship between TA and complication severity.Further research is required to investigate the role of social support in TA and QOL, including the influence of family, friends, healthcare providers, and support groups.Understanding how social support affects TA and QOL can guide the development of interventions to enhance social support networks (Supplementary Information).
79chielsen et al. developedthis 10-item scale in 2003.It has five items on physical fatigue and five items on mental fatigue.The items are scored on a five-point Likert scale from 1 ("Never") to 5 ("Always").Items 4 and 10 are reversely scored.The possible total score of the scale ranges from 10 to 50, with scores less than 22 showing no fatigue and scores 22 and more showing fatigue.In other words, higher scores show greater fatigue74.The reliability and validity of this scale for patients with sarcoidosis in Iran have been confirmed, with a Cronbach's alpha coefficient of 0.92775.The reliability of this scale in the present study was confirmed with a Cronbach's alpha of 0.807, a McDonald's omega of 0.816, and an average inter-item correlation coefficient (AIC) of 0.293.Ware et al. developed this twelve-item scale for QOL assessment based on the original 36-item Health Survey.It predicts 90% of the variance of the 36-item Health Survey79.It has two main dimensions, namely physical health and mental health, with the eight subscales of general health perception, physical functioning, role limitations due to physical health, bodily pain, role limitations due to emotional problems, social functioning, vitality, and mental health.Two items are Yes/No questions and ten items are scored using various Likert scales.Items 1, 8, 10, and 11 are reversely scored.The possible range of the total score is 12-48, with higher scores standing for better QOL.Scores 12-24, 25-36, and 37-48 show poor, moderate, and good QOL, respectively.